(S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the chemical structure,

is also known as γ-amino butyric acid or (S)-3-isobutyl GABA. (S)-Pregabalin, marketed under the name LYRICA®, has been found to activate GAD (L-glutamic acid decarboxylase). (S)-Pregabalin has a dose dependent protective effect on seizure, and is a CNS-active compound. (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity.
Several processes for the synthesis of (S)-Pregabalin are known. For example, U.S. Pat. No. 5,599,973 (“'973 patent”) discloses the preparation of (S)-Pregabalin using a stoichiometric amount of (4R,5S)-(+) 4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary that may be recycled. See, e.g., '973 patent, col. 14, 1.29 to col. 18, 1.23 (example 1). In general, however, the route disclosed in the '973 patent is of limited use on an industrial scale, principally due to the low temperature required for the reaction (e.g., −78° C.), the use of pyrophoric reagent (e.g., butyl lithium), and a low overall yield (e.g., 59%, 65%).
U.S. Publication No. 2003/0212290 (“'290 publication”) discloses the synthesis of (S)-Pregabalin by an asymmetric hydrogenation of a cyano-substituted olefin of formula 7, to produce a cyano precursor of (S)-3-(aminomethyl)-5-methyl hexanoic acid of formula 8, which is further reduced to obtain (S)-Pregabalin, as described in the following scheme.
However, the disclosed method requires the use of carbon monoxide under high pressure, raising serious problems in adapting this process for production scale.
Another process is disclosed by G. M. Sammis, et al., J. Am. Chem. Soc., 125(15): 4442-43 (2003), in which an aluminum salen catalyst is used in the conjugate addition of hydrogen cyanide to α,β-unsaturated imides.
This process is also not practical for large scale production due to the use of highly poisonous reagents. In addition, the last reduction step requires high hydrogen pressure, which only adds to the difficulties required for adapting this process for use on an industrial scale.
International Publication WO 2006/110783 reports several processes for preparing (S)-Pregabalin via the following intermediate and its analogues
wherein R1 and R2 are independently H, a straight or branched C1-10 alkyl, C6-10 aryl, or C3-6 allyl.
U.S. Publication Nos. 2007/0191636 and 2007/0197827 also disclose processes for preparing (S)-Pregabalin.
Thus, there is a need in the art for additional process for the preparation of (S)-Pregabalin that provide (S)-Pregabalin in high quality, and that can be adapted to large (industrial) scale production.